Infections that result in shock and organ failure are a major public health problem worldwide. Severe sepsis and septic shock affect patients of all ages and often complicate chronic diseases. They are the major causes of death in critical care units and contribute substantially to hospital inpatient costs. Translating the scientific advances of the last 4 decades into clinical practice has been challenging. Despite many attempts to develop new therapies, the basic elements of treatment have not changed since the 1960s. In this Grand Rounds, we summarize the results of the clinical trials conducted during the last 4 decades, discuss some lessons learned, and suggest possible directions for future investigation.